The processes of differentiation which result in conversion of uncommitted stem cells to B-lymphocytes expressing membrane-bound immunoglobulin (Ig), and of the latter to antibody-secreting cells, will be studied. The approach will center on the relationship between stage of differentiation and expression of a particular Ig class of B- lymphocytes. Primary differentiation of B-lymphocytes bearing various classes of surface Ig will be examined using antibody mediated suppression of Ig class synthesis in mice. Previous studies using this model have shown that IgM-bearing cells are precursors for cells committed to synthesis of other immunoglobulin classes. The present work will attempt to determine whether there is a sequential switch in expression of immunoglobulins from IgM to IgG to IgA. Mice depleted of B cells by anti-microns treatment have normal T cell functions, and will be used as models for studies on the role of B cells and their products in induction of immunological tolerance. Studies of T Cell "helper function" in anti-microns treated mice will also be done. The role of antigen in causing a switch in express membrane Ig class will be evaluated by comparing ontogeny of B- lymphocytes in conventional and gnobiotic mice, and by determining the class of surface Ig on specific antigen-binding cells (ABC) during an immune response. The incidence of ABC expressing more than one Ig class will be determined. The relationship between class of membrane bound Ig expressed by B-lymphocytes and the class of Ig secreted by those cells when stimulated in vitro will be studied. A continuous effort to relate observations on B-lymphocyte differentiation in animals to defects in differentiation resulting in immunodeficiency diseases and lymphoid malignancy will be maintained.